Throughout this application various publications are referenced by arabic numerals within parentheses. Full bibliographic citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures for the publications in their entireties are hereby incorporated by reference into this application to describe more thoroughly the state of the art to which this invention pertains.
The term "retinoid" has been used to define a group of compounds consisting of retinol (Vitamin A) and both natural and synthetic derivatives thereof. See Sporn, M. B., et al (1). Various metabolic derivatives of retinol have been identified. Of these, retinoic acid has been found to be crucial for normal pattern formation during embryogenesis and in the regulation of the differentiation of a variety of cell types, retinal has been found to be essential for vision, 14-hydroxy-4,14-retro-retinol has been found to have a function in the stimulation of lymphocyte growth, and anhydroretinol has been found to be an antagonist to 14-hydroxy-4,14-retro-retinol. See Gudas, L. J. (2). Other metabolic derivatives of retinol have been dismissed as biologically inactive. See Leo, M. A. et al (3). Two that have been heretofore identified but dismissed as inactive are 4-oxo-retinol and 4-hydroxyretinol.
Retinoic acid (i.e., all-trans-retinoic acid) has been orally administered in clinical trials for the treatment of acute promyelocytic leukemia. See Warrell, R. P. et al, 1991 (4) and Warrell, R. P. et al, 1993 (5). This treatment causes cell differentiation and remission for 3 or 4 months. However, this treatment induces the production of an enzyme which breaks down the retinoic acid and with continued retinoic acid dosages, this induction of enzyme production progressively increases so that the half-life of the retinoic acid becomes progressively shorter; thus the level of retinoic acid reaching the blood progressively decreases and the treatment over time becomes ineffective. See Lefebvre, P. P., et al (6); Muindi, J. R., et al (7); and Brazzel, R. K., et al (8). Other types of leukemia and lymphoma cells from patients respond to all-trans-retinoic acid by differentiating in a cell culture system. See Hong, W. K., et al (9). This indicates that other types of leukemia and lymphoma patients would benefit from retinoid therapy but all-trans-retinoic acid cannot be efficacious in such patients because of its short half-life. Many other types of carcinomas are treated with retinoic acid. See Hong, W. K., et al (9).
All-trans-retinoic acid (also known as tretinoin, Retin-A.RTM.) is also used for treatment of deep (cystic) acne, psoriasis, and other dermatological conditions but the short half-life and side effects of this compound are problems. See Peck, G. L, et al (12). All-trans-retinoic acid is also used for the treatment of liver spots. See Rafai, E. S., et al (13). All-trans-retinoic acid is also used for the treatment of wrinkling which results from photodamage and aging of the skin. See Peck, G. L., et al (12).
The 13-cis-isomer of retinoic acid (also known as isotretinoin, Accutane.RTM.) is used for treatment of deep (cystic) acne, psoriasis, and other dermatological conditions. The 13-cis isomer of retinoic acid has also been found to cause differentiation of epithelial cells, and is used to treat squamous cell carcinoma of the head and neck. See Hong, W. K., et al (9). It is speculated that it isomerizes and is progressively released as all-trans-retinoic acid, thereby lengthening the effective treatment period for this disease compared to where all-trans-retinoic acid is used per se. The 13-cis isomer of retinoic acid has also proven to be useful in the treatment of squamous cell carcinoma of the cervix and of the skin, when used in combination with .alpha.-interferon. See Lippman, S. M., et al (10) and Lippman, S. M., et al (11).
Carcinoma of the breast is treated with 4-hydroxyphenylretinamide, a synthetic retinoid. See Hong, W. K., et al (9).